| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Patients with metastatic or relapsed head and neck cancer and documented progression or relapse after platin and cetuximab-based chemotherapy (combination or sequential treatment)
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| E.1.1.1 | Medical condition in easily understood language |
| Patients with metastatic head and neck cancer progressive under standard therapies |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10067821 |
| E.1.2 | Term | Head and neck cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To determine the activity of BKM120 as measured by the 2-month disease control rate (Complete response + Partial Response + Stable disease according to RECIST 1.1) in adult patients with recurrent or metastatic head and neck cancer progressive under platin and cetuximab-based chemotherapy. |
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| E.2.2 | Secondary objectives of the trial |
o To further assess the activity of BKM120 as measured by progression-free survival (PFS), overall survival (OS), objective response rate (ORR), duration of response, time to progression (TTP) and time to treatment failure (TTF).
o To assess the safety and tolerance of BKM120 in this patient population.
o To assess the 18F-FDG-PET changes reflecting the inhibition of the tumor metabolic activity.
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
1. to define the mutational status (Mutations, amplifications, deletion) of signalling molecules relevant to the PI3K pathway activity i.e. PTEN, p53 and K-ras on archival tumor samples and/or fresh pre-treatment tumor samples collected at pre-screening.
2. To investigate the BKM120 effects on PI3K molecular signalling in pre and on treatment tumor biopsies (optional)
Immunohistochemistry assays will be performed in order to analyse the expression pattern of
o AKT, mTOR, S6rp, 4EBP1, PTEN, PDK1 and their related phospho-proteins (p-AKT Ser473 and Thr308, p-mTOR Ser2448 , p- S6rp Ser 235/236, 4EBP1 Thr 37/46, PTEN Ser380)
o ECGR, pEGFR
o STAT3 and pSTAT3
o GSK3b, Bad and pBad
In addition, potential anti-tumor effects of BKM120 like inhibition of cellular proliferation (Ki-67, cyclin B1, p21) and/or induction of apoptosis (e.g., PARP) will be measured in a similar manner.
3.To investigate the BKM120 effects on angiogenesis markers (blood samples) |
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| E.3 | Principal inclusion criteria |
I1.Adult men and women ≥ 18 years at the day of inform consent signature.
I2.Patients with metastatic or relapsed head and neck cancer.
I3.Documented progression or relapse after platin and cetuximab-based chemotherapy (combination or sequential treatment).
I4.Documented mutational status of PIK3CA before inclusion (molecular pre-screening).
I5.Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
I6.At least one measurable lesion by CT-scan as per RECIST 1.1 .
I7.Life expectancy > 12 weeks.
I8.Adequate bone marrow, renal and liver function as defined by the following tests (to be carried out 7 days prior to starting 1st treatment cycle):
Absolute neutrophil count > 1.0 x 109/L,
Platelet count > 100 x 109/L,
Haemoglobin value above 9 g/dL,
INR > 1.5
Serum Creatinine ≤ 1.5 ULN
Glomerular filtration rate calculated using Cockroft-Gault formula > 60ml/min (or MDRD formulae for patients older than 65 years)
Potassium, calcium, magnesium within normal limits for the institution
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) within normal range (or < 3.0 x ULN if liver metastases are present))
Serum bilirubin within normal range (or ≤ 1.5 ULN if liver metastases are present; or total bilirubin ≤ 3.0 ULN with direct bilirubin within normal range in patients with well documented Gilbert Syndrome- Appendix 03)
Fasting plasma glucose (FPG) ≤ 120 mg/dL or ≤ 6.7 mmol/L.
I9.Women of childbearing potential (entering the study after a confirmed menstrual period and who have a negative urinary pregnancy test within ≤ 72 hours before initiating study treatment) must agree to use two methods of medically acceptable forms of contraception during the whole treatment period and for 1 month (= 5 x t½ of BKM120) after the last treatment intake. NB: Oral contraception, injected or implanted hormonal methods are not allowed as BKM120 potentially decreases the effectiveness of hormonal contraceptives.
I10.Fertile males must use a highly effective contraception during dosing of any study agent + [5 x t1/2] + 12 weeks = contraception through 16 weeks after final dose of study therapy and should not father a child in this period. Female partner of male study subject: highly effective contraception during dosing of any study agent + [5 x t1/2] = contraception + 12 weeks after final dose of study therapy.
I11.Patient should be able and willing to comply with study visits and procedures as per protocol.
I12.Patient should understand, sign, and date the written voluntary informed consent form at the screening visit prior to any protocol-specific procedures performed.
I13.Patients must be covered by a medical insurance.
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| E.4 | Principal exclusion criteria |
E1.Patient having received previous treatment with PI3K and/or mTOR inhibitors
E2.Patient with symptomatic CNS metastases
E3.Patient with a concurrent malignancy or has a malignancy within 3 years of study enrollment, (with the exception of adequately treated basal or squamous cell carcinoma or non-melanomatous skin cancer)
E4.Patient has any of the following mood disorders as judged by the Investigator or a Psychiatrist
oMedically documented history of or active major depressive episode, bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia, a history of suicidal attempt or ideation, or homicidal ideation (immediate risk of doing harm to others)
o≥ CTCAE grade 3 anxiety
oor meets the cut-off score of ≥ 12 in the PHQ-9 or a cut-off of ≥ 15 in the GAD-7 mood scale, respectively,
oor selects a positive response of ‘1, 2, or 3’ to question number 9 regarding potential for suicidal thoughts ideation in the PHQ-9 (independent of the total score of the PHQ-9).
E5.Patient concurrently using other approved or investigational anti-neoplasic agent
E6.Patient who has received wide field radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to starting study drug or who have not recovered to grade 1 or better from related side effects of such therapy (exceptions include alopecia).
E7.Patient having had major surgery within 14 days prior to starting study drug or has not recovered from major side effects of the surgery
E8.Patient with poorly controlled diabetes mellitus (i.e. HbA1c > 8 %)
E9.Patient with active cardiac disease including any of the following:
oLeft Ventricular Ejection Fraction (LVEF) < 50% as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO)
oQTc > 480 (female) or 470 msec (male) on screening ECG (using the QTcF formulae)
oAngina pectoris that requires the use of anti-anginal medication
oVentricular arrhythmias except for benign premature ventricular contractions
oSupraventricular and nodal arrythmias requiring a pacemaker or not controlled with medication
oConduction abnormality requiring a pacemaker
oValvular disease with documented compromise in cardiac function
oSymptomatic pericarditis
E10.Patient with a history of cardiac dysfunction including any of the following;
oMyocardial infarction within the last 6 months, documented by persistent elevated cardiac enzymes or persistent regional wall abnormalities on assessment of LVEF function
oHistory of documented congestive heart failure (New York Heart Association functional classification III-IV)
oDocumented cardiomyopathy
oOther cardiac arrhythmia not controlled with medication
E11.Patient currently receiving treatment with QT prolonging medication known to have a risk to induce Torsades de Pointes (see Appendix 05), and if the treatment cannot be discontinued or switched to a different medication prior to starting study drug
E12.Patient with impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of BKM120 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)
E13.Patient receiving chronic treatment (> 5 days) with steroids or another immunosuppressive agent. Note: Topical applications (e.g., rash), inhaled sprays (e.g., obstructive airways diseases), eye drops or local injections (e.g., intra-articular) are allowed. Patients with previously treated brain metastases, who are on a stable low dose corticosteroids treatment (e.g., dexamethasone 2 mg/day, prednisolone 10 mg/day) for at least 14 days before start of study treatment, are eligible.
E14.Patient has other concurrent severe and/or uncontrolled medical condition that would, in the investigator’s judgment contraindicate her participation in the clinical study (e.g.,chronic pancreatitis, active chronic hepatitis etc.)
E15.Patient has a history of non-compliance to medical regimen
E16.Patient is currently being treated with drugs known to be moderate and strong inhibitors or inducers of isoenzyme CYP3A, and the treatment cannot be discontinued or switched to a different medication prior to starting study drug. Please refer to Appendix 06 for a list of prohibited CYP3A4 inhibitors and inducers.
Note: The oral anti-diabetic drugs troglitazone and pioglitazone are CYP3A inducers.
E17.Patient has a known history of HIV infection
E18.Pregnant or nursing (lactating) woman
E19.Patient has a known hypersensitivity to any of the excipients of BKM120
E20.Patient has not recovered to grade 1 or better (except alopecia) from related side effects of any prior antineoplastic therapy
E21.Patient is currently receiving warfarin or other coumarin derived anti-coagulant, for treatment, prophylaxis or otherwise. Therapy with heparin, low molecular weight heparin (LMWH), or fondaparinux is allowed
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| disease control rate after 2 months of treatments |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
Progression-free survival will be measured from the date of treatment start to the date of event defined as the first documented disease progression or death from any cause. Patients with no event at the time of analysis will be censored at their last tumor assessment date.
Overall survival will be measured from the date of inclusion to the date of death from any cause. Patients who are alive at the time of analysis will be censored at the date of the last contact.
The assessment of safety will be based mainly on the frequency of adverse events based on the common toxicity criteria (CTC-AE-V4.0) grade. Descriptive statistics will be provided for characterizing and assessing patient tolerance to treatment.
Objective response rate is defined as the proportion of patients with complete or partial response according to RECIST 1.1. It will be summarized by a proportion together with its 95% confidence interval.
The duration of response will be measured from the time of first documented response (CR or PR) until the first documented disease progression or death due to underlying cancer. Duration of response will be described in responding subjects using descriptive statistics (median, extreme values, etc.).
The Time to Progression will be measured from the time of treatment start until the first documented disease progression. Patients with no event at the time of the analysis will be censored at their last tumor assessment date.
The Time to treatment failure will be measured from the time of treatment start until discontinuation of treatment for any reason, including disease progression, treatment toxicity, and death. Patients without treatment failure at the time of the analysis will be censored at their last tumor assessment.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 30 |
| E.8.9.1 | In the Member State concerned days | |
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